Methods of producing nor-opioid and nal-opioid benzylisoquinoline alkaloids

Inventors

Smolke, Christina D. • Thodey, Catherine • Trenchard, Isis

Assignees

Antheia Inc

Abstract

A method of demethylizing an opioid to a nor-opioid is provided. The method comprises contacting an opioid with at least one enzyme. Contacting the opioid with the at least one enzyme converts the opioid to a nor-opioid. A method of converting a nor-opioid to a nal-opioid is provided. The method comprises contacting a nor-opioid with at least one enzyme. Contacting the nor-opioid with the at least one enzyme converts the nor-opioid to a nal-opioid.

Core Innovation

The disclosed subject matter involves enzyme-based bioconversion and engineered-host-cell production of benzylisoquinoline alkaloids, including nor-opioids and nal-opioids. It includes demethylation of opioids by O-linked methyl loss and N-linked methyl loss to generate nor-opioids from opioids, and further N-linked methyl modification to generate nal-opioids. The disclosure also includes engineered cells that express demethylases and N-methyltransferases for producing nor-opioids and nal-opioids.

The disclosure further describes epimerization of (S)-1-benzylisoquinoline alkaloids to (R)-1-benzylisoquinoline alkaloids using oxidase/reductase activity and fusion CYP-COR (DRS-DRR) enzymes. It also describes bisbenzylisoquinoline (bisBIA) dimerization and tailoring frameworks in engineered hosts, including coupling reaction types (C–O and/or C–C) and additional enzyme families for coupling/derivatization. Structural formula classes (Va–Vq and Va–Vu) are described for bisBIA scaffolds.

The document links enzyme-catalyzed generation of nor/nal-opioids and derivatization steps using named enzymes, together with impurity-based origin determination. It describes impurity-based distinction between host-cell origins and chemical synthesis, including impurity lists for chemically produced nal-opioids, and discusses engineered-host production and processing systems.

Claims Coverage

The provided claims focus on one independent composition claim directed to a nal-opioid compound defined by the absence of detectable impurities associated with chemical synthesis. The inventive coverage is centered on a single core feature, with dependent claims narrowing the nal-opioid identity and the corresponding impurity set.

The claim coverage centers on a nal-opioid composition defined by the non-detection of a specified set of chemical-synthesis impurity compounds, with dependent claims narrowing the nal-opioid and the named impurities.

Stated Advantages

Documented Applications

No documented applications found